Use of bismuth-containing compounds in topical oral dosage forms for the treatment of halitosis

ABSTRACT

This invention provides for a method for treatment of corneal and dermal wounds by administering bismuth compounds in topical dosage forms. Bismuth compounds cause stimulation of release of growth factors in damaged tissue to promote regeneration of epithelial cells and hence accelerate wound healing. These bismuth compounds also have good antimicrobial activity against several anaerobic bacteria involved in diaper rash exacerbation.

This application is a continuation of application Ser. No. 09/363,077,filed Jul. 28, 1999, abandoned which is a continuation of applicationSer. No. 09/080,583 filed May 18, 1998 now abandoned, which iscontinuation of U.S. Application Ser. No. 08/594,148, filed Jan. 31,1996, now abandoned, which is a continuation-in-part of U.S. ApplicationSer. No. 08/518,971, filed Aug. 24, 1995, now abandoned, which in turnis a continuation-in-part of U.S. Application Ser. No. 08/385,060, filedFeb. 7, 1995, now abandoned which in turn claims priority under 35U.S.C. §119 to Japanese Application No.6-93518, filed May 2, 1994. Allof the above-identified applications are expressly incorporated hereinby reference.

BACKGROUND OF THE INVENTION

Until recently, excessive gastric acidity and mental stress were thoughtto be major pathophysiological reasons for occurrence of peptic ulcers.In the early 1980, Marshall and Warren (Warren, Lancet, 1:1273-1275,1983 and Marshall et al., Lancet, 2:1311-1315, 1984) first reported anunidentified curved bacilli in the stomach of patients with gastritisand peptic ulcers. These bacilli, which later were identified as a gramnegative spiral bacterium and named Helicobacter pylori (Goodwin et al.,Int. J. Syst. Bacteriol. 39:397-405, 1989), have been demonstrated to beassociated with gastritis and peptic ulcers (Buck et al., J. Infect.Dis. 153:664-669, 1986 and Graham, Gastroenterology 96:615-625, 1989),and are thought to be transmitted by person-to-person contact.

Recent clinical investigations have shown a definitive presence of H.Pylori in the dental plaque (Nguyen et al., Journal of ClinicalMicrobiology 31(4):783-787, 1993; Desai et al., Scandinavian Journal ofGastroenterology 26:1205-1208, 1991; and Lambert et al., Lancet341(8850):957, 1993), and have also shown that standard oral hygienepractice does not help reduce H. Pylori presence in the oral cavity(Nguyen et al., Journal of Clinical Microbiology 31(4):783-787, 1993).As a result of these recent discoveries associating bacterial infectionin the causation of peptic ulcer disease, questions regarding thepreviously established paradigms of ulcer treatment and healingprocesses have been raised.

H₂ receptor blockers which suppress acid secretion, such as cimetidine(Tagamet®) and ranitidine (Zantac®), have been used to treat and healduodenal ulcers (Jones et al., Gut. 28:1120-1127, 1987; McIsaac et al.,Aliment. Pharmacol. Therap. 1:369-381, 1987; and Boyed et al.,Amsterdam:Excerpta Medica, 14-42, 1984). Recently, however, a number ofclinical investigations have demonstrated that 70-80% of healed duodenalulcers reoccur within the next year (Goodwin et al., Int. J. Syst.Bacteriol 39:397-407, 1989), and that these drugs do not reverse thetendency for ulcers to form (Wormsley, British Medical Journal 293:1501, 1986; Gudman et al., British Medical Journal i:1095-1097, 1978;and Bardhan et al., British Medical Journal 84:621-623, 1982).

For many years, bismuth compounds have been used for treating ulcers.Clinical investigations comparing the efficacy of CBS (also known astripotassium dicitrato bismuthate (TDB)) with placebo (Lambert,Scandinavian Journal of Gastroenterology 26(Supplement 185):13-21,1991), cimetidine (Bianchi, et al., Lancet 2:698, 1984), and ranitidine(Bianchi et al., Gut. 2:565, 1984; Lee et al., Lancet 1:1299-1301, 1985;and Dobrilla et al., Gut. 29:181-187, 1988) in initial healing andrelapse rates of duodenal ulcers, have shown significantly lower relapserates in patients treated with CBS. The therapeutic efficacy of CBS (andother bismuth compounds), in healing duodenal ulcers and loweringrelapse rates, is attributed to its specific antibacterial activityagainst H. Pylori (McNutty et al., Antimicrobial Agents Chemotherapy28:837-838, 1985; Lambert et al., Antimicrob. Agents Chemotherapy3:510-511, 1986; and Goodwin et al., J. of Antimicrobial AgentsChemotherapy 17:309-314, 1986). The minimum inhibitory concentration(MIC) for CBS against H. Pylori is reported to be 8 mg/L (Lambert etal., Antimicrob. Agents Chemotherapy 3:510-511) and the range is 4-32mg/L (Lambert et al., Antimicrob. Agents Chemotherapy 3:510-511).

In addition to its bacteriocidal activity, CBS has been demonstrated toenhance mucus glycoprotein secretion, strengthen viscoelastic gelproperties of mucus, cause increased concentration of epithelial growthfactor (EGF) in ulcer tissue, and stimulate prostaglandin synthesis inthe gastric antral mucosa (Lee, Scandinavian Journal of Gastroenterology26(Supplement 185):1-6, 1991). These gastroprotective properties of CBSmay contribute to the initial healing of duodenal ulcers and theobserved lower rates of relapse by returning the gastric mucosal cellsto normal physiologic function. The gastroprotective effects of CBS inprevention of gastric lesions induced by various ulcerogenic agents andthe mechanism of ulcer healing have been demonstrated in animal studies(Konturek et al., Digestion 37(Supplement 2):8-15, 1987 and Konturek etal., Scandinavian Journal of Gastroenterology 21(Supplement 122):6-10,1986).

Because of the finding that bismuth is an effective antibacterial agentagainst H. Pylori, concomitant dosages of bismuth-containing compoundswith other anti-ulcer drugs have been increasingly applied in manyclinical cases for treatment of peptic ulcers. The most commonly usedregiments include double or triple therapy with bismuth; meanwhile, somerecent reports regarding quadruple therapy (wherein a proton pumpinhibitor is added to triple therapy) have shown eradication rates ofover 90%, but also cause severe side effects such as vomiting anddiarrhea.

Additionally, while antibacterial therapy (bismuth and amoxycillin ordoxycycline) was shown to be effective in eliminating H. Pylori from thegastric mucosa of duodenal ulcer patients, this therapy had no effect onthe H. Pylori colonies in their dental plaque (Desai et al.,Scandinavian Journal of Gastroenterology 26:1205-1208, 1991, Nguyen etal., Journal of Clinical Microbiology 31(4):783-787, 1993). Thecontinued presence of H. Pylori in the dental plaque raises the questionof whether the relapse of duodenal ulcers is inevitable (Desai et al.,Scandinavian Journal of Gastroenterology 2:1205-1208, 1991 and Abrahamet al., Indian Journal of Gastroenterology 2(4):265-6, Editorial, 1990).

Triple therapy, consisting of an antibiotic (amoxicillin, tetracyclineor erythromycin), metronidazole, and bismuth compounds, has beenreported to result in more than a 95% eradication rate for H. Pylori,and reduced ulcer relapse rate to less than 10% during a 12-monthfollow-up period (Graham et al., Gastroenterology 102:493-496, 1992 andBorody et al., Gastroenterology 102:A 44, 1992). It is interesting tonote that metronidazole as a single agent has only 5% eradication ratefor H. Pylori, but as a component of triple therapy, it increases theeradication rate to as high as 95%. When metronidazole-resistant strainsof H. Pylori are encountered (about 25% of the H. Pylori strains areresistant), the eradication rate falls to about 50% (Logan et al.,Lancet M. 1249-1252, 1991).

One possible explanation for this observed clinical efficacy ofmetronidazole in combination therapy is that metronidazole is activelysecreted in the saliva (Mustofa et al., International Journal ofClinical Pharmacology, Therapy, and Toxicology 29(12):474-478, 1991)where it might be exerting its antimicrobial action against dentalplaque-bound H. Pylori colonies. The typical steady state salivarepresent 10 to 20 times the MIC for H. Pylori. Another antibiotic,Clarithromycin, a new-generation macrolide, which has shown a 40 to 60%cure rate as a single agent, is also secreted in the saliva. Therefore,it is reasonable to believe that in order to achieve nearly completeeradication of H. Pylori, and prevent peptic ulcer relapse, eradicationof this organism from the oral cavity is essential. Colloidal bismuthsubcitrate (CBS), the most effective single agent against H. Pylori, ishowever not absorbed significantly from the GI, and therefore, producesno salivary concentrations. But as a single agent, it is about 6 to 8times more effective in eradicating H. Pylori than metronidazole. Thepresent invention therefore is related to development of a therapeuticmodality to effectively eradicate H. Pylori reservoir from the oralsite, as well as the gastric mucosal wall.

Furthermore, recent clinical studies have implicated this insidiousorganism in gastric cancer (Parsonnet, Gastroenterology Clinics ofAmerica, Helicobacter pylori Infection, Dooley C P, Cohen, H. GuestEditors, Volume 22, No. 1, pp. 89-104, March 1993). A progression ofgastric pathology from gastritis and ulcers to cancer involving H.Pylori has been described (Recavarren-Arie et al., Scandinavian Journalof Gastroenterology 26(Supplement 181),51-57, 1991). In addition to H.Pylori infection, low concentration levels of ascorbic acid in thegastric mucosa has been shown to be a risk factor for gastric cancer(Schorah et al., American Journal of Clinical Nutrition 5(Supplement1):287S-293S, 1991 and Reed et al., Iarc Scientific Publications,105:139-142, 1991). In patients suffering from dyspepsia, chronicgastritis, hypochlorhydria, and duodenal cancer, the intragastricconcentrations of vitamin C were significantly lower (Sobala et al.,Gastroenterology 92(2):357-363, 1989 and O'Conner et al., Gut30(4):436-442, 1989). The present invention therefore also relates totherapies involving both bismuth compounds and ascorbic acid.

SUMMARY OF THE INVENTION

The invention relates to concomitant treatment with bismuth compoundsand/or with other antibacterial compounds and/or with antibiotics intopical oral and peroral dosage forms to eradicate H. Pylori from itsniches both in the dental plaque and in the gastric mucosa in order toimprove the ulcer cure rate and prevent ulcer relapse. The inventionalso provides oral topical dosage forms with pharmaceutically usablebismuth compounds and/or antibacterial compounds and/or antibiotics thateradicate or reduce H. Pylori in dental plaque. The invention furtherprovides for treatment with bismuth compounds and/or antibacterialcompounds and/or antibiotics which are effective against Campylobacterrectus and Treponema denticola which are responsible for causinghalitosis. The invention also provides bismuth compounds which haveapplications in wound healing, particularly in ocular and dermal woundhealing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a generalized reaction diagram for the synthesis of bismuthsulfates.

FIG. 2 is a graph of human saliva concentration versus time which showsthe release of bismuth from CBS chewing gum.

DETAILED DESCRIPTION OF THE INVENTION

Therefore, bismuth compound used in this invention should be apharmaceutically acceptable antimicrobacterial agent against H. Pylori,such as colloidal bismuth subcitrate (CBS), bismuth subcitrate, bismuthcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate,bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassiumdicitrato bismuthate and bismuth aluminate. Preferably, colloidalbismuth subcitrate (CBS), tripotassium dicitrato bismuthate, bismuthsubcitrate, bismuth subsalicylate and their combination are chosen. Morepreferably, CBS and tripotassium dicitrato bismuthate are chosen. Andfurther selection is made for CBS.

The structural formula of CBS is:

[Bi(OH)_(3]) ₃BiC₆H₆O₇(1,2,3-PROPANETRICARBONIC ACID, 2-HYDROXY,BISMUTH(3T)POTASSIUM); CAS#57644-54-9

Other novel bismuth-containing compounds which are useful in the presentinvention are those described in Bos et al., U.S. Pat. No. 4,801,608 andin Serfortein, U.S. Pat. No. 4,153,685, both of which are expresslyincorporated herein by reference. Other bismuth compounds, namelycomplexes of polysulfates, of polyhydroxy compounds such as sugars,sugar alcohols, and ascorbic acid and its derivatives, as well asalpha-D-glucopyranoside bismuth complex, beta-D-fructofuranosyl-oktakis(hydrogen sulfate) bismuth complex, and L-dihydro ascorbyl-tetrakis(hydrogen sulfate) bismuth complex are part of the present invention. Ageneralized reaction diagram for the synthesis of bismuth sulfates isshown in FIG. 1. These novel compounds will deliver bismuth moreeffectively and will have less side effects in treating H. Pyloripositive gastro duodenal diseases. The compounds will lend themselves tocontrolled release oral dosage forms and oral topical dosage forms foreradication of H. Pylori in dental plaque.

Chemical structures of the compounds conceived in this invention arecomplexes of poly-sulfates and of poly-hydroxy compounds such as sugars,sugar alcohols, and ascorbic acid and its derivatives. These novelcompounds will deliver bismuth more effectively and will have less sideeffects in treating H. Pylori positive duodenal ulcers and gastritis.These compounds moreover lend themselves to controlled release oraldosage forms and oral topical dosage forms for eradication of H. Pyloriin dental plaque.

Chemical structures of the compounds conceived in this invention areillustrated below:

The ascorbic acid-derived molecules are synthesized in a mannercompletely analogous to the reaction diagram for synthesis of bismuthsulfates set forth above. These compounds can also be used inembodiments relating to would healing as described below.

In addition to antibacterial bismuth-compounds and antibiotics to theoral cavity for reduction/elimination of Helicobacter pylori in the oralcavity as a means of treatment and prevention of gastrointestinaldiseases including peptic ulcers, recurring gastritis, non-ulcerdyspepsia and gastric cancer. Antibiotics useful herein include, but arenot limited to, Tetracycline, Amoxicillin, Ampicillin, Doxycycline,Erythromycin, Clarithromycin, Metronidazole, Tinidazole, Ciproflaxacin,Oflaxacin, Norflaxacin, Furazolidine, Nitrofurantoin. Antibacterialsuseful herein include, but are not limited to naturally occurringpeptides and synthetic peptide antibacterials such as Lanthocins, andparticularly, Nicin and related peptides, Proton pump inhibitors such asOmeprazole and Lansoprazole, Sanguinaria and other antibacterialsobtained from plant sources, as well as bismuth-containing compounds.

The present methods utilize topical oral dosage forms to deliver bismuthcompounds, antibiotics, and/or antibacterials directly to the oralcavity in concentrations sufficient to reduce or eliminate H. Pylori inin oral cavity.

Each oral-topical dosage form of this invention is the one which canmake it possible to release bismuth compound and/or antibacterialcompounds and/or antibiotics into oral cavity in a predictable mannerand result in appropriate antibacterial concentration. Those examples ofsuch forms include a chewing-gum form, a chewable form includingchewable tablets, lozenges, dental paints, viscous gels, dentalimplants, polymer film adhesives, a troche form, a toothpaste form, agargling-gel form and mouth-rinse form. Preferably, a chewing-gum formand a troche form are chosen. Further, a chewing-gum form is mostpreferred due to its easy-to-use characteristic, predictable drugrelease and increased drug contact with dental surface. The chewing gumdelivery system especially enables sustained contact of theantibacterial agents with the entire oral cavity and therefore, enhancebactericidal/bacteriostatic efficacy. We have already demonstrated thatchewing gum formulation containing an antibacterial agent, colloidalbismuth subcitrate, releases the drug in a precise and reproduciblefashion during a 15 minute chewing time. Chewable tablets, viscous gelformulations, and dental paint formulations also will be able to providesustained concentration of antibacterial agents in the oral cavity.

Oral-topical dosage forms containing bismuth in this invention mustrelease enough bismuth, antibiotic, and/or antibacterial into saliva foreradication of H. Pylori in the oral cavity. The minimum inhibitoryconcentration (MIC) of bismuth for H. Pylori varies in each bismuthcompound. For instance, it is reported that the MIC of CBS for H. Pyloriis 8 mg/L and its range is 4 to 32 mg/L.

Therefore, the dosage form should release bismuth into saliva up to atleast two times the MIC, preferably a minimum of 2 to 10 times, mostpreferably 2 to 250 times. In order to achieve this level of releaserate, the bismuth content per dosage form should be about 50 mg to 200mg, preferably a minimum of 10 mg to 50 mg, most preferably 25 mg to 50mg. For instance, each piece of CBS-containing chewing gum shouldcontain approximately 50 mg to 200 mg of CBS, preferably a minimum of 10mg to 50 mg, most preferably 25 mg to 50 mg.

Time release of each dosage form in this invention must be long enoughto eradicate H. Pylori. Although the duration of time release varies ineach bismuth compound and in each dosage form, it is desirable that atleast 25% of the dose is released within 2 minutes, more preferably atleast 35% , more preferably at least 45%, more preferably at least 55%,more preferably at least 65%, most preferably at least 75%, morepreferably within 2 to 15 minutes, most preferably within 10 to 15minutes.

In other preferred embodiments of the invention presented herein, achewing gum drug delivery system is utilized to provide sustainedconcentration of bismuth compounds, antibiotics, and/or antibacterialcompounds which are proven antibacterial agents against H. Pylori andanti-plaque agents to help these compounds penetrate the dental plaquesto reach the site of H. Pylori infection. The chewing gum deliverysystem enables sustained contact of the antibacterial agents with theentire oral cavity and therefore, enhances bacteriocidal efficacy.

Where antibiotic and/or antibacterial agents other than bismuth are tobe used, oral-topical dosage form in this invention must release enoughantibiotic/antibacterial into saliva for eradication of H. Pylori fromthe oral cavity. The minimum inhibitory concentration. (MIC) varies foreach antibiotic/antibacterial agent. However, for most of theantibiotics listed in this invention, the MIC values are between lessthan 1 to 10 mcg/mL, or 1 to 10 mg/L.

Therefore, the topical-oral dosage from should release theanti-bacterial agent into saliva up to at least 2 times the MIC,preferably a minimum of 2 to 10 times, most preferably 2 to 100 times.In order to achieve this level of release, the antibacterial content perunit of dosage form should be about 10 to 100 mg, preferably a minimumof 5 to 50 mg, most preferably 10 to 25 mg. For instance, each piece ofchewing gum should contain approximately 10 to 100 mg. of the antibioticor antibacterial agent. Preferably a minimum of 5 to 50 mg, mostpreferably 10 to 25 mg.

The topical-oral dosage forms of this invention must release theantibiotic/antibacterial over an extended time. The duration of releaseshould be at least 5 minutes, preferably 10 minutes, most preferably 15minutes. Further, at least 25% of the dose is released within 5 minutes,more preferably at least 35%, more preferably at least 45%, morepreferably at least 55%, more preferably at least 65%, most preferablyat least 75% of the antibiotics/antibacterial content should be releasedwithin 5 minutes, preferably within 2 to 15 minutes, most preferablywithin 10 to 15 minutes.

In other preferred embodiment of this invention, a chewing gum deliverysystem is utilized to provide sustained concentration ofantibiotic/antibacterial agent several times above its MIC for H. Pyloriover at least 10 times.

The anti-plaque agents further contribute to improved efficacy bybreaking down the plaque and exposing the bacterial colonies to theantibacterial agents. The chewing gum formulation containing CBS,antibiotic, and/or antibacterial releases the drug in a precise andreproducible fashion during a 15-minute chewing time. Anti-plaque agentsinclude, but are not limited to, glucanase anhydroglucosidase, glucoseoxidase, silicon oil, sanguinarine, and the like. Chewing gumformulations may optionally include crystalline sorbitol, sorbitolsolution, mannitol, Nova-base™, or any other gum base, dextrans,cellulose derivatives, buffer salts, sweeteners, flavors, and the like.

Optionally, metronidazole can be added to CBS chewing gum to broaden theantimicrobial activity against H. Pylori.

Bismuth compounds embodied in these inventions also have been found tostimulate cellular production of growth factors, and therefore haveapplications in wound healing, specifically in ocular and dermal woundhealing. Therefore, the present invention also contemplates use of novelbismuth complexes with sulfated polyhydroxy hydrophilic film-formingpolymers to accelerate wound healing in ulcerative diseases of the eye,skin, and other mucosal tissues. For these embodiments, the inventioninvolves synthesis of unique complexes of bismuth with partiallysulfated hydrophilic film-forming polymers such as hydroxyprobylcellulose, hydroxyethyl cellulose, hydroxypropyl-methyl cellulose,carboxymethyl cellulose, and polyvinyl alcohol. These compounds areformulated in unique film-forming solutions, aerosols, and gels fortreatment of corneal ulcers, skin ulcers, gastric ulcers, and otherwounds of the skin and mucous membranes. The general structures of thisclass of complexes are represented below:

EXAMPLE 1 Preparation of Therapeutic Substance

To an aqueous solution of ammonia are added bismuth citrate, citricacid, and caustic potash in specific stoichiometric proportions, and atspecific temperatures. The solution is examined for turbidity and, ifrequired, additional volume of ammonia solution is added to render thesolution clear. The solution is then filtered on a carbon bed and spraydried to obtain free-flowing powder material. The product is packaged inan air and moisture proof glass container.

EXAMPLE 2 Preparation of Topical Dosage Form

Brief general description of the preferred topical dosage form, chewinggum, is set forth as follows. Fully melt the gum base (at approximately90° C.) in Brabender mixer, a jacketed mixer with sigma blades. Removethe hot water from the mixer jacket, allow to cool, and add lecithin andmix well. Cool further to approximately 50° C., and add liquid flavorand mannitol. Mix until uniform. Dry blend colloidal bismuth subcitratein sorbitol, and blend sodium citrate in sorbo syrup. Add sorbitol andsorbo syrup blends to the gum base. Cool the product to 35° C., addflavor and sweetener and mix until smooth. Remove the product from themixing kettle, roll to form a sheet of uniform thickness and score toproduce chewing gum sticks weighing 2.5 g each. Wrap individual gumsticks in aluminum foil and place in plastic bags. Where the gum is toinclude antibiotic or antibacterial compounds, the agent is coated witha polymeric substance to mask any untoward taste or odor, and to furtherregulate its release in the saliva.

EXAMPLE 3 Composition of CBS-Containing Gum

Two variations of the 50 mg CBS gum (Table 1) were used. Bothformulations used were identical with the exception that Formula-2contained sodium citrate to impart a firmer texture, while Formula-1 didnot.

TABLE 1 FORMULATIONS OF THE GUM (APPROX. 2.5 gm A PIECE) Formula-1Formula-2 CBS 50.0 mg CBS 50.0 mg Crystalline Sorbitol 910.0 CrystallineSorbitol 910.0 Gum Base 575.0 Gum Base 575.0 Sorbitol Solution 500.0Sorbitol Solution 500.0 Mannitol 400.0 Mannitol 400.0 Peppermint Oil25.0 Peppermint Oil 25.0 Spray Dried 12.5 Spray Dried 12.5 PeppermintPeppermint Grade t Lecithin 10.0 Grade t Lecithin 10.0 Aspartame 10.0Aspartame 10.0 Sodium Citrate 10.0 2502.5 mg Total: 2492.5 mg

Colloidal Bismuth Subcitrate (CBS) and other bismuth compounds,including bismuth subcitrate, bismuth citrate, bismuth salicylate,bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuthtartrate, bismuth subgallate, tripotassium dicitrato bismuthate andbismuth aluminate. Preferably, colloidal bismuth subcitrate (CBS),tripotassium dicitrato bismuthate, bismuth subcitrate, bismuthsubsalicylate are coated with the following coating agent to regulatetheir dissolution and salivary release: bee's wax, carnauba wax,shellac, cellulose acetate phthalate, methyl cellulose, propylcellulose, hydroxy propyl-cellulose, ethyl cellulose, hydroxypropylmethylcellulose, ethylcellulose, polymethyl methacrylate, andEudragit® polymers, polyvinyl pyrohidone, polyvinyl alcohol, etc.

Moderately water soluble bismuth compounds such as bismuth ascorbylsulfate, bismuth sucrose sulfate, bismuth subascorbate, cyclodextrinbismuth sulfate are used in the chewing gum dosage form to producesustained concentration in the saliva.

Synthetic and natural latex-based chewing gum bases are used to tightlyenclose bismuth compounds and other antibacterial/antibiotic compoundsto cause their gradual release in the saliva.

These formulation/composition modifications are designed to:

(1) provide control release of antibacterial/antibiotic compounds toincrease their bactericidal efficacy against oral cavity/dental plaquebound H. Pylori; and

(2) avoid/minimize oral cavity discoloration/blackening caused by quickor instant release of bismuth compounds in the saliva.

EXAMPLE 4 Measurement of Release Rate of Bismuth into Saliva

Among six healthy human subjects, who gave informed consent, threechewed the CBS-containing gum with sodium citrate, and the other threechewed CBS-containing gum without sodium citrate. The subjects chewedthe gum samples for a total of 15 minutes. Saliva samples were collectedat time interval of 0, 1, 5, 10, and 15 minutes of chewing. The salivasamples were then submitted to an analytical laboratory for bismuthanalysis. Results are shown in Table 2.

TABLE 2 IN VIVO SALIVARY CONCENTRATION OF CBS FROM THE CHEWING GUMchewing time saliva conc of Bi conc of active Formula (min.) vol. (mL)(ppm) CBS (u/mL) X MIC formula-1 0 4.4 (±0.5) 1 3.3 (±1.4) 900.7(±239.1) 1270.3 (±334.7) 148.7 (±42.0) 5 5.4 (±1.5) 257.7 (±112.3) 363.3 (±158.9)  45.0 (±19.9) 10 4.9 (±1.3)  28.0 (±5.0)  40.0 (±6.6) 5.0 (±1.0) 15 5.2 (±2.1)  15.8 (±17.8)  25.7 (±23.0)  3.1 (±2.7)formula-2 0 7.2 (±0.5) 1 4.8 (±1.9) 888.3 (±329.5) 1257.0 (±464.5) 156.3(±58.0) 5 8.5 (±1.7) 326.0 (±113.3)  572.7 (±159.7)  63.7 (±19.9) 10 7.5(±3.4)  30.0 (+9.5)  42.3 (±13.6)  5.0 (±1.7) 15 7.7 (±3.8)  10.7 (±6.7) 14.7 (±9.2)  1.8 (±1.2)

Saliva samples were analyzed for elemental bismuth in ppm units. Theresults were then converted to mg of active CBS per mL of saliva andalso expressed as a multiple of minimum inhibitory concentration (MIC)of CBS for H. Pylori. As can be seen from the results (formula-2 ofTable-3), the salivary concentrations of CBS are 156, 64, 5, and 1.8times the MIC at 1, 5, 10 and 15 minutes, respectively. The constantbathing of the oral cavity from saliva containing sufficientconcentration of CBS (2 to 5 times the MIC) for up to 15 minutes can beexpected to further reduce the viable cells of H. Pylori. These resultsare plotted in FIG. 2 which shows a graph of human saliva concentrationversus time.

EXAMPLE 5 Sensory Analysis of Chewing Gum

Sensory characteristics of the chewing gum were evaluated by thesubjects during the 15 minutes of chewing. Again, three subjects chewedthe CBS gum containing sodium citrate and three subjects chewed the CBSgum without sodium citrate. A nine point rating scale was used toevaluate each category (Tables 3 and 4).

TABLE 3 RESULTS OF SENSORY ANALYSIS RATING OF CBS GUM WITHOUT SODIUMCITRATE (Formula-1) CHEWING TIME SENSORY CHARACTERISTICS 1 MIN 5 MIN 10MIN 15 MIN Overall Flavor 6.3 6.0 5.3 5.0 (0 = dislike extremely, (±1.2)(±1.0) (±1.5) (±1.0) 8 = like extremely) Flavor Intensity 5.7 4.7 3.73.0 (0 = none, 8 = very strong) (±1.5) (±1.2) (±0.6) (±1.0) ChewQualities 6.0 6.0 5.3 5.0 (0 = dislike extremely, (±1.0) (±1.0) (±1.5)(±1.0) 8 = like extremely) Unpleasant Aftertaste 0.0 0.0 0.0 0.0 (0 =none, 8 = very strong) (±0.0) (±0.0) (±0.0) (±0.0) Overall Qualities 6.36.0 5.7 5.3 (0 = dislike extremely, (±1.2) (±1.0) (±1.2) (±1.5) 8 = likeextremely)

TABLE 4 RESULTS OF SENSORY ANALYSIS RATING OF CBS GUM WTTH SODIUMCITRATE (Formula-2) CHEWING TIME SENSORY CHARACTERISTICS 1 MIN 5 MIN 10MIN 15 MIN Overall Flavor 6.7 5.7 4.7 4.7 (0 = dislike extremely, (±0.6)(±1.5) (±1.2) (±1.2) 8 = like extremely) Flavor Intensity 6.7 6.0 5.03.7 (0 = none, 8 = very strong) (±0.6) (±0.0) (±1.0) (±1.5) ChewQualities 4.7 5.0 4.3 4.3 (0 = dislike extremely, (±2.1) (±2.0) (±1.5)(±0.6) 8 = like extremely) Unpleasant Aftertaste 0.7 1.7 1.7 2.0 (0 =none, 8 = very strong) (±1.2) (±2.1) (±2.1) (±2.0) Overall Qualities 6.35.7 4.7 4.0 (0 = dislike extremely, (±0.6) (±1.2) (±1.2) (±1.0) 8 = likeextremely)

In general, there were no dramatic differences in the sensory analysisbetween the two formulas. The sensory panel clearly shows that bothchewing gum formulations have a desirable level of flavor and taste, andcause a minimal unpleasant aftertaste after chewing.

EXAMPLE 6 Topical Safety

Topical safety was evaluated in the six volunteers for up to 60 minutesafter administration of the gum. The subjects were asked to report anyadverse effects such as discomfort or irritation in the oral cavity.

There were no reports of any discomfort or irritation in the oral cavityby any of the subjects at either the 15 or 60 minute post administrationtime periods.

EXAMPLE 7 Storage Stability Study

Samples of CBS-containing gum (50 mg) were wrapped individually in foilwrappers. The sticks of gum were then placed in foil laminate bags,sealed, and placed in storage. Storage conditions include 40° C. androom temperature (RT). The duration of the stability testing was 90days. The results are shown in Tables 5-8 below.

TABLE 5 THREE MONTH STABILITY DATA IN VIVO SALIVARY CONCENTRATIONS INHUMAN SUBJECTS OF CBS FROM THE 50 MG CBS CHEWING GUM (Mfg. August 1993,Batch No. CBS-50CG-0002) CHEWING SALIVA CONC OF Bi CONC OF Bi CONC OFACTIVE TIME/CONDITION TIME (min) VOLUME (mL) (ppm) (mg/mL) CBS (mg/mL) XMIC ZERO TIME 0 4.2 (±1.6) NA NA NA NA 1 4.9 (±4.5) 1537.3 (±753.5)1937.3 (±753.5) 2729.0 (±1060.2) 341.0 (±132.7) 5 6.4 (±3.1)  437.0(±152.1)  437.0 (±152.1)  615.7 (±214.5)  77.0 (±26.9) 10 3.9 (±0.1) 36.0 (±28.6)  36.0 (±28.6)  50.7 (±40.5)  6.4 (±5.0) 15 4.5 (±1.3)  5.0 (±4.6)   5.0 (±4.6)   7.0 (±6.6)  0.9 (±0.8) 3 MONTHS/ 0 5.6(±1.4) NA NA NA NA 40° C. 1 2.9 (±1.8) 1922.3 (±511.8) 1922.3 (±511.8)2710.0 (±791.9) 338.6 (±90.3) 5 5.6 (±1.7)  399.3 (±278.1)  363.7(±113.3)  563.0 (±329.3)  70.3 (±49.1) 10 5.3 (±1.4)  25.7 (±11.4)  30.0(±9.5)  362.0 (±160.5)  45.4 (±20.1) 15 4.9 (±0.4)   7.9 (±4.9)   10.7(±6.7)   10.8 (±6.8)  1.4 (±0.9) 3 MONTHS/ 0 5.1 (±1.3) NA NA NA NA ROOMTEMP. 1 4.1 (±1.5) 1240.0 (±458.7) 1240.0 (±458.7) 1748.0 (±646.6) 218.0(±80.6) 5 7.2 (±2.3)  518.7 (±111.7)  518.7 (±118.7)  731.3 (±167.6) 91.0 (±21.0) 10 6.0 (±2.2)  12.5 (±10.6)  12.5 (±10.6)  17.7 (±14.6) 2.1 (±1.8) 15 5.6 (±1.6)   4.5 (±2.2)   4.5 (±2.2)   6.0 (±2.6)  0.7(±0.3) N = 3 for each quote

TABLE 6 THREE MONTH STABILITY DATA RESULTS OF SENSORY ANALYSIS RATING OF50 MG CBS GUM (Mfg. August 1993, Batch No. CBS-50CG-0002) CHEWING TIMESENSORY CHARACTERISTIC 1 MIN 5 MIN 10 MIN 15 MIN ZERO TIME OVERALLFLAVOR 6.7 (±0.6) 6.3 (±0.6) 5.3 (±0.6) 5.3 (±0.6) FLAVOR INTEGRITY 6.3(±1.2) 5.3 (±1.2) 4.0 (±1.0) 4.0 (±1.0) CHEW QUALITIES 6.7 (±0.6) 6.3(±0.6) 5.7 (±0.6) 5.3 (±0.6) UNPLEASANT AFTERTASTE 0.0 (±0.0) 0.0 (±0.0)0.0 (±2.1) 0.0 (±0.0) OVERALL QUALITIES 6.7 (±0.6) 6.3 (±0.6) 5.7 (±0.6)5.3 (±1.2) 3 MONTHS/40° C. OVERALL FLAVOR 6.0 (±0.0) 4.7 (±0.6) 2.7(±1.2) 2.7 (±1.2) FLAVOR INTEGRITY 5.3 (±1.2) 3.0 (±0.0) 2.3 (±0.6) 2.0(±1.0) CHEW QUALITIES 5.7 (±0.6) 5.0 (±1.0) 4.3 (±0.6) 4.3 (±0.6)UNPLEASANT AFTERTASTE 0.3 (±0.6) 0.3 (±0.6) 0.0 (±0.0) 0.0 (±0.0)OVERALL QUALITIES 6.0 (±0.0) 4.3 (±0.6) 2.7 (±0.6) 2.3 (±0.6) 3MONTHS/ROOM TEMP. OVERALL FLAVOR 6.3 (±0.6) 6.3 (±0.6) 5.3 (±0.6) 4.3(±0.6) FLAVOR INTEGRITY 5.7 (±1.5) 5.3 (±1.5) 4.3 (±1.5) 4.0 (±1.7) CHEWQUALITIES 6.0 (±1.0) 6.0 (±1.0) 5.3 (±0.6) 4.3 (±0.6) UNPLEASANTAFTERTASTE 0.0 (±0.0) 0.0 (±0.0) 0.0 (±0.0) 0.0 (±0.0) OVERALL QUALITIES6.3 (±0.6) 6.3 (±0.6) 5.3 (±0.6) 4.7 (±1.2) Note: n = 3 for eachanalysis Rating Scale: 0 = dislike extremely, 8 = like extremely for:Overall Flavor, Chew Quality, Overall Quality 0 = none, 8 = likeextremely for: Flavor Intensity 0 = none, 8 = very strong for:Unpleasant Aftertaste

TABLE 7 EXPONENTIAL REGRESSION DATA OF TIME VS SALIVARY CONCENTRATIONSEXPRESSED AS X MIC Stability Lot # Initial Test Lot # CBS-50CG-0002Clinical Lot # CBS-50CG-0001 Zero Time 3 mo./RT 3 mo./40° C.CBS-50CG-0003 A (intercept) 240.0 563.1 575.7 422.3 446.5 B (slope)−0.339 −0.432 −0.361 −0.448 −0.426 r (correlation 0.992 0.998 0.9480.971 0.959 coefficient) K (pseudo first order −0.339 −0.432 −0.361−0.448 −0.426 rate constant) t_(0.5) (min.) 2.04 1.60 1.92 1.55 1.63Mean t_(0.5) = 1.748 (±0.218)

TABLE 8 RELEASE OF CBS FROM THE CHEWING GUM AFTER 15 MINUTES OF CHEWINGBY HUMAN SUBJECTS Stability Lot # CBS-50CG-0002 Clinical Lot # Zero Time3 mo./RT 3 mo./40° C. CBS-50CG-0003 Mg CBS/2.5 g gum 45.6 (100) 44.5(100) 46.1 (100) 46.2 (100 Before chewing (%) Mg CBS/2.5 g gum  3.5(7.6)  4.0 (9.0)  4.5 (9.8)  3.8 (100) After 15 min chewing (%) Mean %of CBS Remaining in the gum after 15 min of chewing = 8.6 (±1.0)

Each stick of the gums used for the stability study (1 for zero-time, 2for three month, total 3 sticks) was from the same lot number. Theresults show that bismuth concentration remains stable over the testedtime period.

EXAMPLE 8 Denture Material Exposure Study

An evaluation of CBS salivary concentration on various denture materialswas conducted in order to test any potential staining effect of the CBSon denture materials. Artificial saliva was used (Table 9).

TABLE 9 THE C0MPOSITION OF ARTIFICIAL SALIVA Ingredients Concentrationper Liter Sodium Bicarbonate 0.50 g Sodium Phosphate, Dibasic, Dihydrate0.85 g Calcium Chloride 0.44 g Magnesium Chloride 0.06 g PotassiumChloride 1.40 g Sodium Carboxyl Methyl Cellulose 2.00 g Phosphoric Acidto adjust pH to 6.4 QS Distilled Water

The test saliva was prepared by dissolving 0.500 g of colloidal bismuthsubcitrate in 100 mL of the above artificial saliva. 500 mL ofArtificial Saliva (RT) was placed in one of two identical glass jarswith lids. In the other jar was placed 500 mL of the Artificial Saliva(RT) containing 0.50% of CBS. In each of the jars the denture materialblock and a magnetic stirrer was placed. The jars were then placed onthe magnetic platform and set to agitate at a minimum rate. The denturematerials that were exposed to artificial saliva containing CBS orplacebo included (Table 10).

Table 10 Denture Materials

1) Natural tooth with silver amalgam filling

2) Composite resin (used on anterior teeth for filling)

3) Denture base acrylic resin

4) Porcelain fused to metal

5) Partial denture metal frame

6) Acrylic tooth (artificial)

7) Natural tooth

The four hour exposure of natural tooth and other denture mnaterials to0.5% CBS in artificial saliva with mild agitation did not cause anystaining, discoloration, or changes in texture.

EXAMPLE 9 Clinical Efficacy Data

An open label, placebo-controlled pilot clinical study in ten patientswith initial positive response for H. Pylori in the dental plaque hasbeen initiated. Data from six patients (four patients treated with CBS50 mg chewing gum six times-a-day and two patients treated with placebochewing gum six times-a-day for fifteen days) has been obtained. Thedental plaque samples from the patients were collected before treatment,day 7 and day 15 after treatment, and tested by microbiological cultureand CLO test. The results are set forth in Table 11 below:

TABLE 11 SIDE DUR POSITIVE EFFECTS CLO (HRS:MINS) CULTURE (Stain/Odor)TREATED GROUP (n = 4) Mean CL0 response time after 15 days = 4.125 HR Pt1 Day 0 + 1:00 + NE 30/M Day 7 + 1:45 −ve — Day 15 + 1:30 −ve — Pt 2 Day0 + 2:15 + NE 42/M Day 7 + 1:30 NA — Day 15 + 4:00 −ve — Pt 3 Day 0 +2:30 + NIL 31/M Day 7 + 4:30 NA NIL Day 15 + 5:30 NA NIL Pt 4 Day 0 +2:30 NA NIL 29/F Day 7 + 4:00 NA NIL Day 15 + 5:30 NA NIL PLACEBO (n =2) Mean CLO response time after 15 days = 2.0 HR Pt 1 Day 0 + 1:00 NANIL 26/M Day 7 + 1:30 NA NIL Day 15 + 1:30 NA NIL Pt 2 Day 0 + 1:15 NANIL 28/M Day 7 + 2:00 NA NIL Day 15 + 2:30 NA NIL NA = Not available NE= Not evaluated (before chewing)

The data show that for patients treated with CBS 50 mg chewing gum andplacebo chewing gum on day 15 the mean CLO response times are 4.125hours and 2.0 hours, respectively. The longer CLO test response time forCBS 50 mg chewing gum group compared to the placebo chewing gum group isindicative of substantial reduction in H. Pylori density in the oralcavity of the active treatment group.

EXAMPLE 10 Toxicology

A number of animal toxicity studies and human clinical investigationshave demonstrated safety of bismuth compounds, especially CBS, intherapeutic dose ranges. No toxicity has been reported in chronic dailyadministration of high doses of CBS (160, 320, and 640 mg/kg body weightrepresenting 2, 4, and 8 times the human therapeutic dose respectively)in rats treated for three months or dogs treated for six months. SeeWieriks et al., Journal of Gastroenterology 17(Supplement 80):11-16(1982), incorporated herein by reference.

Long term safety of CBS and treatment of peptic ulcers at a standarddose of 480 mg (expressed as bismuthtrioxide) in four daily divideddoses has been examined by Bader, Digestion 37(Supplement 2):53-59(1987), incorporated herein by reference. CBS was first introduced inEurope in 1971 and since that time 1.5 million treatments have beendispensed. During eight years of use of CBS tablets [De-Nol®] in Europebetween 1978 and 1986 under a more comprehensive adverse reactionmonitoring system, only 13 adverse reaction forms were completed. Fiveof these adverse reactions were ascribed to CBS: one case of headache,one case of stomach pain, one case of diarrhea, and two cases of allergy(mainly in the form of skin rashes). A high degree of safety of CBS intherapeutic applications for the treatment of peptic ulcers is reportedin a recent review of pharmacology of bismuth-containing compounds byLambert, Review of Infectious Diseases 13(Supplement 8):691-695 (1991),incorporated herein by reference. In reviewing safety andpharmacokinetics of CBS, Bennet, Scandinavian Journal ofGastroenterology 26(Supplement 185):29-35 (1991), incorporated herein byreference, has calculated the systemic bioavailability of bismuth afteroral dosing of CBS to be in the range of 0.16 to 0.28% of theadministered dose, and concluded that steady-state blood levels of50-100 mg/mL are unlikely to cause any neurotoxicity.

EXAMPLE 11 Composition of Antibiotic or Antibacterial-Containing Gum

The chewing gum formulation comprises antibiotic or antibacterial agentsin concentration ranges from 10 to 50 mg per piece of gum. The chewinggum-base consists of Crystalline Sorbitol, Gum Base, Sorbitol Solution,Mannitol, Peppermint Oil, Spray Dried Peppermint, Grade t Lecithin,Aspartame, and Sodium Citrate, as set forth in Table 1 above. Theformulation may also contain Glucanase, Anhydroglucosidase, Glucoseoxidase, Silicon oil, Sanguinarine and related compounds as anti-plaqueagents. Caboxy methyl cellulose, Hydroxy propyl methyl cellulose,Polyethylene glycol, Poly methyl methacrylates, Acrylic acid copolymersand other polymers as coating agents.

Saliva samples are analyzed for antibiotic or antibacterial agents inppm units. The results are then converted to mg of active agent per mLof saliva and also expressed as a multiple of minimum inhibitoryconcentration (MIC) of the agent for H. Pylori. The salivaryconcentrations of the agent are 156, 64, 5, and 1.8 times the MIC at 1,5, 10 and 15 minutes, respectively. The constant bathing of the oralcavity from saliva containing sufficient concentration of the agent (2to 5 times the MIC) for up to 15 minutes can be expected to furtherreduce the viable cells of H. Pylori. These results are plotted to showa graph of human saliva concentration versus time.

Sensory characteristics of the chewing gum are evaluated by the subjectsduring the 15 minutes of chewing. Again, three subjects chews the gumcontaining sodium citrate and three subjects chewed the gum withoutsodium citrate. A nine point rating scale is used to evaluate eachcategory.

In general, there are no dramatic differences in the sensory analysisbetween the two formulas. The sensory panel shows that both chewing gumformulations have a desirable level of flavor and taste, and cause aminimal unpleasant aftertaste after chewing.

Topical safety is evaluated in the six volunteers for up to 60 minutesafter administration of the gum. The subjects are asked to report anyadverse effects such as discomfort or irritation in the oral cavity.

There are no reports of any discomfort or irritation in the oral cavityby any of the subjects at either the 15 or 60 minute post administrationtime periods.

Samples of the agent-containing gum (50 mg) are wrapped individually infoil wrappers. The sticks of gum are then placed in foil laminate bags,sealed, and placed in storage. Storage conditions include 40° C. androom temperature (RT). The duration of the stability testing is 90 days.

Each stick of the gums used for the stability study (1 for zero-time, 2for three month, total 3 sticks) is from the same lot number. Theresults show that bismuth concentration remains stable over the testedtime period.

An evaluation of salivary concentration of the agent on various denturematerials is conducted in order to test any potential staining effect ofthe CBS on denture materials. Artificial saliva is used (Table 9).

The test saliva is prepared by dissolving 0.500 g of the antibiotic orantibacterial agent in 100 mL of the above artificial saliva. 500 mL ofArtificial Saliva (RT) is placed in one of two identical glass jars withlids. In the other jar is placed 500 mL of the Artificial Saliva (RT)containing 0.50% of the agent. In each of the jars die denture materialblock and a magnetic stirrer is placed. The jars are then placed on themagnetic platform and set to agitate at a minimum rate. The denturematerials that are were exposed to artificial saliva containing theagent or placebo are included. The four hour exposure of natural toothand other denture materials to 0.5% of the agent in artificial salivawith mild agitation does not cause any staining, discoloration, orchanges in texture.

To assess clinical efficacy, patients with positive response for thepresence of H. Pylori in the dental plaque/oral cavity are divided intotwo treatment groups. Group I is given placebo chewing gum to be chewed2 or 6 times a day for 2 or 4 weeks. Group II is given chewing gumcontaining antibiotic/antibacterial agent to be chewed 2 or 6 times aday for 2 or 4 weeks. Patient's dental plaque/saliva samples arecollected at time 0 (Pre-treatment) on days 7, 14, 28, and tested for H.Pylori presence and density. The incidence of H. Pylori presence in theplacebo group and the active treatment group is compared. The groupreceiving the chewing gum containing antibiotic/antibacterial showssignificantly lower incidence of H. Pylori presence in the dentalplaque/saliva compared to placebo chewing gum group after 2 and 4 weeksof treatment.

EXAMPLE 12 Antibacterial Efficacy for Treatment of Halitosis

Campylobacter rectus, Helicobacter pylori, and Treponema denticola havebeen demonstrated to be associated with Halitosis (bad breath). Thecompounds and methods of the present invention, including CBS as well asascorbyl bismuth derivative, have demonstrated in vitro activity againstall three bacteria, as indicated by their minimum effectiveconcentrations (MICs) presented in Table 12 below.

TABLE 12 Bismuth Bismuth Ascorbyl Sulfate Sucrose Sulfate CBS TestOrganisms (μg/mL) (μg/mL) (μg/mL) Campylobacter rectus 256 >256 256Helicobacter pylori 8 16 2 Treponema denticola 16 32 32

EXAMPLE 13 In Vitro Mesentery Culture Model

Colloidal bismuth subcitrate and other bismuth compounds are known toaccelerate wound healing by increasing the concentration of epithelialgrowth factor (EGF) and fibroblast growth factor (FGF) in the woundedtissue.

Utilizing a rat mesentery culture model (Wu et al., Annals of PlasticSurgery 33(2):155-161 (1994), incorporated herein by reference) and amedium containing 2% fetal calf serum, wound closure rates are measured.This tissue culture model is useful for gaining insights into growthfactor interactions and wound healing. CBS or bismuth ascorbyl sulfateor glucose (placebo) are added to the medium in concentration rangesfrom 10 mcg/mL to 1,000 mcg/mL, and the wound closure is assessed at24-hour, 48-hour and 72-hour intervals. Significantly higherconcentrations of growth factors EGF and FGF are observed. Moreover, asignificantly faster wound closure rate and complete closure is seen inthe culture to which CBS or bismuth ascorbyl sulfate are added, comparedto the placebo.

EXAMPLE 14 Diabetic Mouse Wound Healing Model

Further, wound healing potential of the above bismuth compounds isevaluated using a diabetic mouse wound healing model (Matuszewska etal., Pharmaceutical Research 11(1):65-71 (1994), incorporated herein byreference). Wounds treated with CBS and bismuth ascorbyl sulfateformulations at concentration ranges of 10 mcg/mL to 1,000 mcg/mL healfaster compared to placebo treated wound. The wound healing ratesproduced by the bismuth compounds are comparable to the wound healingrate produced by 0.5 to 5 mcg/mL concentration of basic fibroblastgrowth factor (bFGF).

EXAMPLE 15 Freeze-injured Skin Graft Model

The efficacy of CBS and bismuth ascorbyl sulfate at enhancing woundhealing is also studied in a freeze-injured skin graft model forquantitative evaluation of promoters of wound healing (Lees et al.,British Journal of Plastic Surgery 47(5):349-359 (1994), incorporatedherein by reference). Application of CBS or bismuth ascorbyl sulfatestimulates wound healing in cryoinjured grafts in a dose-relatedfashion. Doses of 10 to 1000 mcg/mL produce significant increase inwound healing rates compared to placebo.

Topical dosage forms for wound healing will depend on whether corneal ordermal wound healing is sought. For dermal wound healing, occlusive ornon-occlusive barriers can be used to achieve a pharmacologicallydesirable concentration over a desirable duration (i.e., sustainedrelease). For corneal wound healing, it is desirable to release thedosage of bismuth compound over a period of at least 30 minutes, morepreferably at least 1 hour, more preferably at least 6 hours, morepreferably at least 12 hours, more preferably at least 24 hours, morepreferably at least 36 hours, more preferably at least 48 hours, morepreferably at least 60 hours, more preferably at least 72 hours. Forboth dermal and corneal treatment, the release of bismuth compoundsshould provide a concentration of at least 10 μg/mL, more preferably atleast 100 μg/mL, more preferably at least 500 μg/mL, more preferably atleast 1 mg/mL, more preferably at least 10 mg/mL, more preferably atleast 100 mg/mL.

Dermal wound healing as disclosed herein also contemplates the treatmentof acne vulgaris to eliminate bacteria and to repair epithelial celldamage. For this use, the topical dosage form should be able topenetrate the acne comedone (i.e., pustule having crusty surface),should permit comfortable application, and should not cause irritationof acne. As disclosed herein, suitable dosage forms include creams,gels, ointments, suspensions, etc., and will provide therapeuticconcentrations as set forth above.

Thus, while several embodiments have been shown and described, variousmodifications may be made, without departing from the spirit and scopeof the present invention.

What is claimed is:
 1. A method of treating halitosis caused by bacteriain an oral cavity, comprising administering to the oral cavity a topicaloral dosage form selected from the group consisting of chewing gum,chewable tablets, lozenges, troches, toothpastes, gargling gels, mouthrinses, and combinations thereof, wherein the topical oral dosage formcomprises a pharmaceutically active agent effective against the bacteriaconsisting essentially of a bismuth compound selected from the groupconsisting of colloidal bismuth subcitrate, bismuth subcitrate, bismuthcitrate, bismuth salicylate, bismuth subsalicylate, bismuth subnitrate,bismuth subcarbonate, bismuth tartrate, bismuth subgallate, tripotassiumdicitrato bismuthate, bismuth aluminate, bismuth polysulfates, bismuthpolyhydroxy compounds, alpha-D-glucopyranoside bismuth complex,beta-D-fructofuranosyl-oktakis (hydrogen sulfate) bismuth complex,L-dihydro ascorbyl-tetrakis (hydrogen sulfate) bismuth complex, bismuthascorbyl sulfate, bismuth subascorbate, bismuth sucrose sulfate, bismuthcyclodextrin sulfate, and combinations thereof; and providing sustainedrelease from the topical oral dosage form into the saliva in the oralcavity for at least 5 minutes of a therapeutically-effective amount ofthe bismuth compound in a concentration in the saliva of at least 2μg/mL.
 2. The method of claim 1, wherein the bismuth compound isreleased into the saliva in the oral cavity in an amount at least 10times the minimum inhibitory concentration for said bacteria.
 3. Themethod of claim 2, wherein said topical oral dosage form is a chewinggum or a lozenge.
 4. The method of claim 2, wherein said topical oraldosage form is selected from the group consisting of a toothpaste, agargling gel, and a mouth rinse, and wherein the dosage form furthercomprises a film forming polymer.
 5. The method of claim 2, wherein saidtopical oral dosage form is selected from the group consisting of achewable tablet and a troche, and wherein the dosage form furthercomprises hydrophilic polymers in a suitable concentration.
 6. Themethod of claim 2, wherein said bismuth compound is colloidal bismuthsubcitrate and wherein said dosage form is a chewing gum.
 7. The methodof claim 2, wherein said bismuth compound is selected from the groupconsisting of bismuth polysulfates, bismuth polyhydroxy compounds,alpha-D-glucopyranoside bismuth complex, beta-D-fructofuranosyl-oktakis(hydrogen sulfate) bismuth complex, L-dihydro ascorbyl-tetrakis(hydrogen sulfate) bismuth complex, bismuth ascorbyl sulfate, bismuthsubascorbate, and bismuth cyclodextrin sulfate.
 8. The method of claim1, further comprising maintaining said dosage form in said oral cavityin said bismuth compound-releasing condition for at least 10 minutes. 9.The method of claim 2, further comprising maintaining said dosage formin said oral cavity in said bismuth compound-releasing condition for atleast 10 minutes.
 10. The method of claim 1, further comprisingadministering said dosage form to a person in need thereof between twoand six times per day for a period between two and four weeks.
 11. Themethod of claim 10, wherein said dosage form includes between 10 mg. and50 mg. of said bismuth compound per dose.
 12. The method of claim 1,wherein said bacteria is Campylobacter rectus, Helicobacter pylori, orTreponema denticola.
 13. The method of claim 1, wherein the topical oraldosage form is a chewing gum.
 14. The method of claim 1, wherein thetopical oral dosage form is a chewable tablet.
 15. The method of claim1, wherein the topical oral dosage form is a troche.
 16. The method ofclaim 1, wherein the topical oral dosage form is a lozenge.